The invention relates to novel flavones and to processes of making them.
Flavonoids, such as flavones, are natural products produced by living organisms. Many of these compounds are natural products that do not appear to have any obvious metabolic or evolutionary function and may be formed by xe2x80x9cmetabolic accidentxe2x80x9d or are by-products of the synthetic machinery of the cellular enzymes. Regardless of their utility to the parent organism, their value to man as drugs, herbs, flavorings, poisons, dyes, and the like is undisputed.
The subject flavones comprise oxygenated derivatives of aromatic ring structures. Derivatives of flavone are found throughout the plant kingdom and especially in the higher plants. Although many biologically active flavone derivatives have been found in nature, they also have been produced synthetically. Certain of these compounds are useful as respiratory stimulants (U.S. Pat. No. 3,147,258), as an inhibitor of MAP kinase (Mahboobi, S., Pongratz, H., Synthesis of 2xe2x80x2-Amino-3xe2x80x2methoxyflavone (PD 98059), Synth. Commun., 1999;29:1645), and as an antitumor agent (Akama T., et a., Structure-activity relationships of the 7-substituents of 5,4xe2x80x2-diamino-6,8,3xe2x80x2trifluoroflavone, a potent antitumor agent, J. Med. Chem., Jun. 4, 1998; 41(12):2056-67). An acetylcholine esterase inhibitor compound was described in Rampa A., et al., Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl) methyl] aminoalkoxyheteroaryl derivatives, J. Med. Chem., Oct. 8, 1998; 41(21):3976-86, in which the flavone structure has a phenyl group bearing an N-methylcarbamoyloxy radical connected with the oxygen atom of the flavone skeleton via a five membered chain: 
Flavonoids serve as antioxidants and chemoprotectants against molecular damage from reactive oxygen species (ROS). Their antioxidative activity has been the subject of many studies (e.g., van Acker SA, et al., Structural aspects of antioxidant activity of flavonoids, Free Radic. Biol. Med., 1996;20(3):331-42).
Oxidative stress, manifested by, for example. protein oxidation and lipid peroxidation is one characteristic of the brain of a person suffering from Alzheimer""s Disease (AD) (Cf. Varadarajan S, et al., Alzheimer""s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity, J. Struct. Biol., June 2000; 130(2-3):184-208. The beneficial effect of various antioxidants in the treatment of AD is now widely recognized. Cf. Pratico D, Delanty N., Oxidative injury in diseases of the central nervous system: focus on Alzheimer""s disease, Am. J. Med., November 2000; 109(7):577-85; Giacobini E., Present and future of Alzheimer therapy, J. Neural. Transm. Suppl., 2000; 59:231-42; Aisen, P S., et al., Anti-inflammatory and antioxidant therapies in Alzheimer""s disease, Funct. Neurobio. Aging, 487-492 (Hof and Mobbs edS., Academic Press: San Diego, Calif. 2001). Various compounds incorporating a carbamoyl functionality (e.g., rivastigmine and physostigmine) are useful for the treatment of AD via enhancement of cholinergic transmission through inhibition of acetylcholinesterase (AChE).
The compounds of the present invention were designed as potential therapeutic agents for the treatment of AD by combining both ACHE inhibitory activity and antioxidant activity (by virtue of their carbamoyl and flavonoid pharmacophores).
The invention relates to compounds of the general Formula I: 
wherein each of R1, R2, R3, R4 and R5 is a substituent selected from the group consisting of:
hydrogen;
OOCNR6(R7), in which each of R6 and R7 is hydrogen, or a lower alkyl (C1-C4) and in which each of R6 and R7 may be the same or different;
OR8, wherein R8 is hydrogen or a lower alkyl (C1-C4); 
wherein each of R9 and R10 is hydrogen or a lower alkyl (C1-C4);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR11, wherein R11 is hydrogen, sodium, potassium, or a lower alkyl (C1-C4);
CONR12R13, wherein each of R12 and R13 is hydrogen or a lower alkyl (C1-C4);
NO2; and
CN; and
wherein at least one of R1, R2, R3, R4 and R5 is OOCNR6(R7).
The invention relates to new flavone derivatives of Formula I above which have at least one N-disubstituted carbamoyloxy unit (OOCNR6(R7)) coupled directly to one or both aromatic rings of the flavone molecule. Accordingly, the invention embraces compounds of Formulae IA, IB and IC, below. Compounds of Formula IA are characterized by the formula: 
wherein R4 is OOCNR6(R7), in which each of R6 and R7 is hydrogen or a lower alkyl of 1 to 4 carbon atoms and in which each of R6 and R7 may be the same or different, and wherein R4 occurs in the 2xe2x80x2, 3xe2x80x2 or 4xe2x80x2 position; and
wherein each of R1, R2, R3, and R5 is a substituent selected from the group consisting of:
hydrogen;
OR8, wherein R8 is hydrogen or a lower alkyl of 1 to 4 carbon atoms, 
wherein each of R9 and R10 is hydrogen or a lower alkyl (C1-C4);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR11, wherein R11 is hydrogen, sodium, potassium, or a lower alkyl (C1-C4);
CONR12R13, wherein each of R12 and R13 is hydrogen or a lower alkyl (C1-C4);
NO2; and
CN.
Compounds of Formula IB are characterized by the following formula: 
wherein R1 is OOCNR6(R7), in which each of R6 and R7 is hydrogen or a lower alkyl (C1-C4) and in which each of R6 and R7 may be the same or different, and wherein R1 occurs in the 5, 6, 7, or 8 position; and
wherein each of R2, R3, R4 and R5 is a substituent selected from the group consisting of:
hydrogen;
OR8, wherein R8 is hydrogen or a lower alkyl (C1-C4); 
wherein each of R9 and R10 is hydrogen or a lower alkyl (C1-C4);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR11, wherein R11 is hydrogen, sodium, potassium, or a lower alkyl (C1-C4);
CONR12R13, wherein each of R12 and R13 is hydrogen or a lower alkyl (C1-C4);
NO2; and
CN.
The compounds of Formula IC are characterized by the following formula: 
wherein each of R1 and R4 is OOCNR6(R7) and R1 occurs in the 5, 6, 7, or 8 position and R4 occurs in the 2xe2x80x2, 3xe2x80x2, or 4xe2x80x2 position, and each of R6 and R7 is hydrogen or a lower alkyl (C1-C4) and in which each of R6 and R7 may be the same or different; and
wherein each of R2, R3, and R5 is a substituent selected from the group consisting of:
hydrogen;
OR8, wherein R8 is hydrogen or a lower alkyl (C1-C4); 
wherein each of R9 and R10 is hydrogen or a lower alkyl (C1-C4);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR11, wherein R11 is hydrogen, sodium, potassium, or a lower alkyl (C1-C4);
CONR12R13, wherein each of R12 and R13 is hydrogen or a lower alkyl (C1-C4);
NO2; and
CN.
The definitions of each of R6, R7, R8, R9, R10, R11, R12, R13 indicates that each may be an alkyl of 1 to 4 carbon atoms, for example, methyl, ethyl, isopropyl, butyl, isobutyl or t-butyl.
Compounds of the invention are prepared by reacting a hydroxyflavone reactant with dialkylcarbamoyl chloride (R6R7NCOCl) in the presence of a base such as sodium hydride or potassium carbonate, according to the following reaction scheme: 
The reaction is carried out in an organic solvent such as dimethylformamide, acetonitrile or in a mixture of dimethylformamide and acetonitrile. The reaction can be undertaken at room temperature or up to about the boiling or reflux temperature of the solvent. For example, when the solvent contains acetonitrile, the reaction can be carried out at up to about 82xc2x0 C., as determined by the boiling point of acetonitrile.
The hydroxyflavone reactant, used for production of the invention compounds in the reaction scheme set forth above, can be prepared by many methods. Various methods of hydroxyflavone synthesis are described in xe2x80x9cThe Chemistry of Flavonoid Compounds,xe2x80x9d Geissman, ed., Perg. Press (1962), which is relied upon and incorporated by reference herein. According to the synthetic method, shown below, the starting material is an appropriately substituted 2-hydroxyacetophenone derivative. The 2-hydroxyacetophenone derivative is the precursor for production of a phenolester derivative. In turn, the phenolester derivative is synthesized by reacting an aromatic acid chloride with the 2-hydroxyacetophenone derivative in a manner described, for example, in Org. Synth. Coll., vol. IV, 478 (1963), which is relied upon and incorporated by reference herein. That phenolester is treated with alkali hydroxide(s) in pyridine to effect a Baker-Venkataraman rearrangement to produce a 1,3-diketone, as described in J. Chem. Soc., 1381 (1933) and in Curr. Sci., 4, 214 (1933), each of which is relied upon and incorporated by reference herein. 
Ring closure of the 1,3-diketone, in the presence of mineral acid in acetic acid as a solvent, results in a flavone derivative having at least one alkoxy group. This compound is subjected to a dealkylation resulting in the desired hydroxyflavone compound as a precursor for the synthesis of new dialkylaminocarbamoyloxy derivatives of flavones.
Specific embodiments of the invention include compounds of Formula II: 
wherein R1, R2, R3 and R4 are selected from the group consisting of:
hydrogen;
OOCNR5(R6), wherein each of R5 and R6 is a lower alkyl (C1-C4) and in which each of R5 and R6 may be the same or different;
OR7, wherein R7 is a lower alkyl (C1-C4); 
wherein each of R8 and R9 is hydrogen or a lower alkyl (C1-C4);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR10, wherein R10 is hydrogen, sodium, potassium, or a lower alkyl (C1-C4);
CONR11R12, wherein each of R11 and R12 is hydrogen, or a lower alkyl (C1-C4);
NO2; and
CN; and
wherein at least one of R1, R2, R3 and R4 is OOCNR5(R6).
Specific compounds of Formula II are set forth in Table I:
In the table, Me is methyl and Et is ethyl.
Compounds of Examples 1 and 2 below were prepared by the following synthetic route: 
Compounds of Examples 5, 6, 7 and 8 below were prepared by the following synthetic route: 
Compounds of Examples 9 and 10 below were prepared by the following synthetic route: 
Compounds of the invention were tested for acetylcholine esterase inhibition and did exhibit acetylcholine esterase inhibition. By way of background, acetylcholine may either increase muscle contraction (frog skeletal muscle) or decrease it (frog cardiac muscle) depending on the identity of the choline receptor affected and treated (Molecular Biology, Scientific American Books (Third Edition), p. 957 (1997)). During hydrolysis of acetylcholine by acetylcholine esterase, the acetyl group reacts with serine to produce toxins and inhibitors. Such toxins prolong the action of acetylcholine, prolonging the period of membrane depolarization. Such inhibitors can be lethal if they prevent relaxation of the muscles necessary for breathing (Id. at 965).
As pharmaceutical reagents, the carbamoyl derivatives of flavones of the invention can be compounded or diluted with pharmaceutically acceptable carriers and diluents, both liquid and solid, and formed into capsules or tablets for oral administration or formulated as solutions for parenteral administration, by intravenous or intramuscular administration. The invention also embraces inhibiting acetylcholine esterase activity by administering a compound of Formula I to a mammalian host in need of acetylcholine esterase inhibition.
The results of the acetylcholine esterase inhibitory activity testing are set forth in Table II:
The foregoing ex vivo results recommend application of therapeutically effective amounts of composition of the invention to mammalian hosts, including human hosts, to inhibit acetylcholine esterase activity, and diseases associated with such activity, for example, AD. The following examples are illustrative of the invention. However, the examples simply present specific embodiments of the invention. The invention embraces the subject matter of the appended claims and all equivalents thereof.